Research on Birth Defects Shifts to Flaws in Sperm

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AFTER three decades of efforts to discover how a pregnant woman's environment can affect the health of her fetus, researchers are turning their attention to fathers.

The new research, much of it in early stages, suggests that certain substances can cause genetic mutations or other alterations in sperm that lead to permanent defects in children.

These include familiar birth defects like heart abnormalities and mental retardation as well as less familiar ones like childhood cancer and learning disorders.

The new findings may force health authorities and occupational safety experts to rethink or expand regulations intended to prevent birth defects that have limited women, but not men, from jobs considered hazardous to the fetus.

Each year in the United States, at least 250,000 babies are born with physical birth defects while thousands more develop behavioral and learning defects that appear to have a genetic component. The cause of 60 to 80 percent of birth defects is not known, although many scientists suspect that environmental toxins play a role in a sizable number of them. The male contribution may be substantial, researchers now say.

Society has focused on the mother and fetus because they are easier to study, said Dr. Devra Lee Davis, a scholar in residence at the National Academy of Sciences who edited a recent book on biological markers in reproductive toxicology.

Since thalidomide vividly demonstrated that drugs a woman takes during pregnancy can harm her fetus, scientists have discovered more than 30 drugs, viruses, chemicals and other substances that can cross the placenta and cause structural damage to the fetus. Researchers estimate that another 900 chemicals are toxic to human development.

As a result, some American companies have developed fetal protection policies that banish women of child-bearing age from the factory floor, even if they do not intend to have children.

Animal experiments and human epidemiological research had previously linked men's exposures to certain substances with birth defects in their children, said Dr. Donald R. Mattison, dean of the School of Public Health at the University of Pittsburgh. Most of the earlier research has been ignored, he said, because scientists could not identify any possible biological mechanism to explain it.

Scientists also held to what some refer to as a "macho sperm theory of conception," the idea that only the fittest sperm were hardy enough to go the distance necessary to fertilize an egg. In fact research now shows that tiny hairs in the female reproductive tract move sperm along whether they are healthy or defective.

"You don't have to be Sigmund Freud to figure out there are cultural factors to say why we have paid so much attention to the female and so little to the male," Dr. Davis said.

The tools of molecular biology are now pointing to plausible mechanisms in which damage to sperm could lead to birth defects, said Dr. Marvin Legator, a genetic toxicologist at the University of Texas Health Sciences Center in Galveston. Scientists can pluck single diseased genes from cells, examine the hundreds of newly discovered proteins in sperm, place special markers on sperm to follow their development and watch how chemicals interact with sperm proteins and DNA. Vulnerability of Sperm

Researchers have found several childhood cancers that primarily arise from new mutations traced to sperm, never to eggs.

They believe defects may originate during the division of the cells that generate sperm cells. Cells are most vulnerable to genetic damage when they divide beacuse they are more likely to absorb and metabolize toxic substances than are quiescent cells.

Eggs do not divide; all eggs a woman has are present before birth.

By contrast, next to the cells in developing fetus the stem cells that produce sperm are among the most rapidly dividing cells in the human body. Moreover, researchers now realize that the barrier between blood vessels and tissue in the testes is very thin, allowing many toxic substances to enter testicular structures and seminal fluid.

Animal studies have identified more than 100 chemicals that produce spontaneous abortion or birth defects in offspring fathered by exposed males, said Dr. Mattison. Among them are alcohol, opiates like heroin and methadone, gases used in hospital operating rooms, lead, solvents, pesticides and a variety of industrial chemicals.

In some instances, litter size is greatly reduced or the offspring are deformed. In other cases, the young animals appear healthy but cannot negotiate mazes as well as control animals.

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One case pending before the United States Supreme Court involves restrictive work rules intended to protect women of childbearing age from exposure to lead, which can cause neurological defects. But in one recent study, Dr. Ellen Silbergeld, a toxicologist at the University of Maryland in Baltimore, exposed male rats to relatively low levels of lead, equivalent to amounts encountered by many factory workers. The male rats' offspring showed defects in brain development, even if the female rats were not exposed to lead at all, Dr. Silbergeld said.

Other scientists have conducted scores of epidemiological studies looking for links between a father's occupation and birth defects in children. They have found numerous associations:

Wives of men exposed to vinyl chloride and waste water treatment chemicals have more miscarriages. Welders who breathe toxic metal fumes develop abnormal sperm, even after exposure stops for three weeks. Firemen who are exposed to toxic smoke have an increased risk of producing children with heart defects. Several studies have found that fathers who take two or more alcoholic drinks a day have smaller than average infants.

A British study recently found that men exposed to low levels of radiation at a single nuclear power plant had a higher than expected number of children with leukemia. The greater the exposure, the greater the risk. Some American investigators claim to have found a link between fathers' exposure to the defoliant Agent Orange in Vietnam and a variety of birth defects in their children. Both studies are controversial, and large Government-sponsored studies on Agent Orange have failed to confirm the link.

A spate of new research is finding that some rare forms of childhood cancer are closely linked with the father's genes and occupations. Garage mechanics, auto body workers and other men exposed to hydrocarbons, solvents, metals, oils and paints have a four to eightfold increased risk of having children with Wilm's tumor, a kidney cancer. Fathers who work with lead have an almost fourfold increased risk of producing such children.

An abormal gene associated with a rare eye cancer, retinoblastoma, can be inherited from a parent who already carries it, or it can arise as a spontaneous mutation in the parent's egg or sperm. Researchers are finding that the spontaneous form seems to always stem from a mutation in the father's sperm, said Dr. Merlin Butler, pediatrician and genetics expert at Vanderbilt University in Atlanta.

Similarly, a genetic disorder called Prader Willi syndrome stems from errors found in the father's chromosomes, said Dr. Butler. The syndrome has been linked to children of men who work with solvents and hydrocarbons.

But epidemiological studies cannot prove cause and effect, said Dr. John Peters, an epidemiologist at the University of Southern California. In real life, people are exposed sporadically to combinations of substances that might interact, he said. A child can encounter toxic chemicals by contact with the father's clothing.

Unlike the case of thalidomide, in which the association was unmistakable, the findings linking a father's occupation and birth defects are statistically significant but not dramatic, Dr. Peters said. He said at least a dozen of the recent studies are particularly well done and "strongly suggest" that fathers contribute to birth defects, including childhood cancers. To show more dramatic associations, he said, scientists would need to study hundreds of thousands of people over many years.

Molecular biologists are conducting experiments that may explain the mechanisms involved, said Dr. Andrew J. Wyrobek, a researcher at the Lawrence Livermore Laboratory in Livermore, Calif. Methods are being developed to detect sperm with missing or extra chromosomes, study chromosome regions that tend to get shuffled around in the presence of chemicals, locate single gene mutations and identify how chemicals might attach themselves to proteins or DNA within sperm.

Ultimately it will be possible to follow sperm from their earliest formation through fertilization, explaining how and where damage occurs, the researchers said. For example, if the stem cells that give rise to sperm suffer permanent genetic mutations, errors would always be present in a significant number of sperm. It should be possible to pinpoint such mutations.

If toxins are drawn to specific regulatory genes because of a chemical affinity, then specific patterns of genetic damage could result. For example, a solvent might attach itself to a master gene that determines the fate of many subsequent cells in heart tissue. Heart defects would be a common outcome of exposure to the chemical. Other chemicals could affect sites that determine whether genes are expressed. Yet others could induce transposable elements in chromosomes -- regions that naturally jump around -- to break or form harmful combinations.

In another case, which has been shown to happen in laboratory experiments, a chemical attaches itself to a protein within the sperm head. Upon fertilization the chemical is carried into the egg where it could exert an effect on the earliest stages of embryo growth.

Researchers used to think of sperm as being relatively simple, stripped-down vehicles for carrying male DNA into an egg, said Dr. Anthony Bellve, a Columbia University urologist who is a leading expert on sperm genetics. But new research shows that each sperm head contains 300 to 400 novel proteins. Each sperm membrane contains another 300 to 400 proteins. It is entirely possible, said Dr. Bellve, that these proteins exert powerful influences on early embryogenesis.

According to Dr. Silbergeld, lead could have such an effect by attaching itself to zinc binding proteins found in sperm, fetuses and adults. Tiny amounts of lead in an early embryo, she said, could alter zinc pathways and affect brain development.

While scientists explore such mechanisms, people should not panic, Dr. Mattison said. But it may make sense to clean up the work place for fathers as well as for mothers.

A version of this article appears in print on January 1, 1991, on Page 1001001 of the National edition with the headline: Research on Birth Defects Shifts to Flaws in Sperm. Order Reprints|Today's Paper|Subscribe